Role of Dendritic Cells in Immunity to Pulmonary Influenza Virus Infections

描述（由申请人提供）：呼吸道是病原体（包括许多潜在的生物武器）的重要入口。在这些病原体中，流感病毒不仅就流行性流感而言，而且还因为大流行性爆发的日益增加的威胁而代表严重的公共卫生威胁。先前的研究表明，对致命流感病毒感染的保护部分是由CDS T细胞杀死流感感染的细胞介导的。这种T细胞应答的诱导、幅度和效应表型又通常被认为与树突状细胞（DC）对病毒攻击的应答密切相关。然而，我们目前对DC如何特异性地调节呼吸道T细胞反应以及对致死（高毒性）和亚致死流感病毒感染的反应的理解是非常有限的。因此，我们的长期目标是了解DC调节CDS T细胞对肺部感染的反应的机制，这取决于肺部挑战的性质。通过这种调节，DC似乎最终决定了强毒流感病毒感染的结果，因为我们的初步结果表明，在致死剂量流感病毒感染期间，流感特异性CDS T细胞应答被抑制。这种抑制依赖于淋巴结DC（LNDC）的FasL表达和LNDC驱动的发展中T细胞应答的凋亡。因此，在本提案中，我们将继续利用我们的流感病毒感染小鼠模型来确定DC如何在致死和亚致死流感病毒感染后调节流感特异性CDS T细胞应答，具体目的如下：1）确定在致死性流感病毒感染后哪个或哪些LNDC子集介导病毒特异性CDS T细胞应答的LNDC消除，以及这种消除是否是抗原特异性的确定调节IL-12 p40依赖性LNDC FasL表达的机制3）确定DC在致死和亚致死流感感染期间启动病毒特异性CDS效应子应答中的作用。该提案将阐明在致死和亚致死流感病毒感染期间DC如何调节和控制流感特异性CDS T细胞应答。此外，它将产生对DC调节机制的重要见解，这些调节机制在旨在增强保护性肺免疫的疫苗接种和治疗期间需要被抑制，特别是在致命的流感病毒感染和疫苗接种期间。

DESCRIPTION (provided by applicant): The respiratory tract serves as a significant entry point for pathogens including many potential bioweapons. Among these pathogens, Influenza virus represents a serious public health threat not only with regard to epidemic influenza but also because of the increasing threat of pandemic outbreaks. Previous studies have shown that protection from lethal influenza virus infections is mediated in part by CDS T cell killing of influenza-infected cells. The induction, magnitude, and effector phenotype of this T cell response in turn is generally thought to be intimately linked to the dendritic cell (DC) response to virus challenge. However our current understanding of how DC specifically regulate respiratory T cell responses in general and responses to lethal (highly virulent) and sub-lethal influenza virus infections in particular is quite limited. Therefore our long-term goal is to understand the mechanisms through which DC regulate, dependent upon the nature of the pulmonary challenge, the CDS T cell response to pulmonary infections. Through such regulation, DC appear to ultimately determine the outcome of virulent influenza virus infections as our preliminary results show that influenza-specific CDS T cell responses are inhibited during lethal dose influenza virus infections. This inhibition is dependent upon FasL expression by lymph node DC (LNDC) and LNDC driven apoptosis of the developing T cell response. Therefore in this proposal we will continue to utilize our mouse model of influenza virus infection to determine how DC regulate influenza-specific CDS T cells responses following lethal and sublethal influenza virus infections in the following Specific Aims: 1) Determine which LNDC subset(s) mediate LNDC elimination of virus-specific CDS T cell responses following lethal influenza virus infections and if this elimination is antigen-specific 2) Determine the mechanisms regulating IL-12p40 dependent LNDC FasL expression 3) Determine the role of DC in the initiation of virus-specific CDS effector responses during lethal and sublethal influenza infections. This proposal will elucidate how DC regulate and control the influenza-specific CDS T cell response during lethal and sublethal influenza virus infections. Furthermore it will yield important insights into the DC regulatory mechanisms that will need to be inhibited during vaccinations and treatments aimed at enhancing protective pulmonary immunity, particularly during lethal influenza virus infections and vaccinations.